Chronic lymphocytic leukemia (CLL)

This article will help you read and understand your pathology report for chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).

By Rosemarie Tremblay-LeMay MD FRCPC, updated December 23, 2020

Quick facts:

• Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are two names given to the same type of cancer.
• Both start from cells in the immune system.
• Chronic lymphocytic leukemia is a type of cancer of the blood called a leukemia.
• Small lymphocytic lymphoma is a type of cancer called a lymphoma.
• When the cancer cells are found in the blood the disease is called chronic lymphocytic leukemia.
• When the cancer cells are found in lymph nodes and other organs, but not in the blood, the disease is called small lymphocytic lymphoma.

The immune system

Your immune system is made up of many different kinds of cells including lymphocytes, plasma cells, neutrophils, eosinophils, and macrophages. Each type of cell plays a special and important role protecting your body from infections and helping it heal after an injury.

Unlike other types of organs, your immune system is spread throughout your body. Most immune cells are found in small bean shaped structures called lymph nodes, although many are also found in the blood, skin, gastrointestinal tract, and bones.

What is chronic lymphocytic leukemia/small lymphocytic lymphoma?

CLL/SLL is a type of cancer that starts from specialized immune cells called a B-lymphocytes. CLL is a type of leukemia while SLL is a type of non-Hodgkin lymphoma.

In reality, CLL and SLL is one disease with two names. This is because both CLL and SLL are made up of the same type of cancer cells. The only real difference between CLL and SLL is where the cancer cells are found. When the cancer cells are found in lymph nodes and other solid organs but not in the blood the disease is called SLL (a lymphoma). When the cancer cells are found in the blood the disease is called CLL (a leukemia).

Patients that present with SLL can eventually develop CLL, or vice-versa, and patients can present with both at the same time. For that reason, the disease is often described under the name CLL/SLL.

Symptoms of chronic lymphocytic leukemia/small lymphocytic lymphoma

The symptoms of CLL/SLL may be mild, and many patients do not experience any symptoms until later in the disease. For many people the disease will be discovered during a routine blood test.

Common signs and symptoms of CLL/SLL include:

• Swollen lymph nodes palpable in the neck, groin or under the arm; enlarged spleen.
• Fatigue, weight loss, fever, or night sweats.
• Frequent and prolonged infections.
• Increased bruising or bleeding.

People with CLL may develop autoantibodies that cause the immune system to attack their own cells. This can lead to a type of anemia called hemolytic anemia where red blood cells are destroyed. It can also lead to a disease called immune thrombocytopenia, which can result in bruising and bleeding. Many people can also have issues with their immune system that can make them vulnerable to infections.

How do pathologists make this diagnosis?

The diagnosis of CLL/SLL can be made after a blood test or after a small sample of tissue is removed in a procedure called a biopsy. The tissue sample will often be from the bone marrow or an enlarged lymph node.

Your doctor may suspect that you have CLL/SLL if your blood test shows an increased number of lymphocytes. Pathologists call this lymphocytosis. If lymphocytosis is found, another test called flow cytometry may be performed on your blood sample. This test allows your pathologist to determine if the lymphocytes are abnormal. See the Flow cytometry section below for more information.

When examined under the microscope, the cancer cells in the blood are small and they have little substance in a part of their cell body called the cytoplasm. The cells are fragile and tend to break when the blood is spread on a glass slide. Pathologists call these broken cells smudge cells.

Instead of being evenly spread out, the genetic material or chromatin in the nucleus of the cell will also appear as small dots. Pathologists describe this look as clumpy and may say that the chromatin looks like a soccer ball (dark dots on a pale background).

Prolymphocytes

A small number of larger lymphocytes called prolymphocytes are also usually seen. These cells usually make up less than 15% of the cancer cells seen in the sample. If the number of prolymphocytes is greater than 15% but is still less than 55%, your pathologist will describe the changes as atypical CLL.

Atypical CLL cells are more likely to have an extra copy of chromosome 12 (trisomy 12) and the cells may produce proteins that are not typically produced by CLL cells. If more than 55% of the cancer cells in the sample are prolymphocytes, the diagnosis changes to B-cell prolymphocytic leukemia, which is a different, more aggressive type of cancer.

The cancer cells seen in a tissue sample such as a lymph node are very similar looking to those seen in the blood. The cancer cells are mostly small, except for groups of larger cells called proliferation centres. A test called immunohistochemistry is often performed on the tissue sample to confirm the diagnosis. See the Immunohistochemistry section below for more information.

Transformation

Overtime, CLL/SLL can change into a more aggressive type of lymphoma. Pathologists call this a transformation. Your pathologist will carefully examine the sample to look for any evidence of transformation.

CLL/SLL can transform in one of the ways:

• Prolymphocytoid transformation.
• Diffuse large B-cell lymphoma.
• Classic Hodgkin lymphoma.

Because these conditions are more aggressive, they require different treatment than CLL/SLL without transformation.

Immunohistochemistry

Your pathologist will perform a test called immunohistochemistry to learn more about the tumour and to exclude other diseases that can look similar to CLL/SLL under the microscope. Immunohistochemistry is a test that allows pathologists to see the different types of proteins produced by cells in a tissue sample. When the cells produce a protein, pathologists describe the result as positive or reactive. When the cells do not produce the protein, the result is described as negative or non-reactive.

Because the cancer cells in CLL/SLL come from specialized immune cells called B-lymphocytes, they produce proteins normally made by this type of cell. These proteins include CD20, CD19, PAX5 and CD79a. The expression of CD20 is usually weaker than normal, healthy B-lymphocytes. The cancer cells also usually produce CD5, CD23, CD43 and LEF1. CD10 and CyclinD1 are found in other types of B-cell lymphomas and are not produced by the cancer cells in CLL/SLL.

Flow cytometry

Flow cytometry is a special test that is used to examine the immune cells in a blood, bone marrow, or tissue sample. Another name for this test is flow immunophenotyping. Unlike other types of laboratory tests, flow cytometry can examine millions of individual cells very quickly and collect information about each cell. The information collected includes the cell size and shape and the types of proteins being made by each cell.

When examined by flow cytometry, the tumour cells in CLL/SLL will have strong expression of the protein CD200. Expression of the protein CD38 in more than 30% of the tumour cells can be associated with more aggressive disease.

Molecular tests

Each cell in your body contains a set of instructions that tell the cell how to behave. These instructions are written in a language called DNA and the instructions are stored on 46 chromosomes in each cell. Because the instructions are very long, they are broken up into sections called genes and each gene tells the cell how to produce piece of the machine called a protein.

Pathologists test for changes involving chromosomes by performing fluorescence in situ hybridization (FISH). When FISH is performed on CLL/SLL an abnormal number of chromosomes may be found. The test may also show that a piece of a chromosome has been lost.

The most common changes seen in CLL/SLL are:

• Trisomy 12 – The cancer cells have an extra copy of chromosome 12.
• 13q deletion – Part of chromosome 13 is lost.
• 11q23 or ATM – Part of chromosome 11 is lost.
• 17p deletion – Part of chromosome 17 is lost The lost genetic material includes a gene called TP53.

Tumours with cancer cells that have lost part of chromosome 11 or chromosome 17, and those that show complex changes (multiple gains or losses), can behave more aggressively than tumours without these changes.

Some tumours will show a change (a mutation) in a gene called immunoglobulin heavy chain. This gene produces a protein that helps B-cells recognize foreign proteins in the body (such as those on viruses). Tumours with this mutation are less aggressive and may have more favorable prognosis compared to tumours without the mutation.